Reconfiguration of Structural and Functional Connectivity Coupling in Patient Subgroups With Adolescent Depression

Abstract

Importance: Adolescent major depressive disorder (MDD) is associated with serious adverse implications for brain development and higher rates of self-injury and suicide, raising concerns about its neurobiological mechanisms in clinical neuroscience. However, most previous studies regarding the brain alterations in adolescent MDD focused on single-modal images or analyzed images of different modalities separately, ignoring the potential role of aberrant interactions between brain structure and function in the psychopathology.

Objective: To examine alterations of structural and functional connectivity (SC-FC) coupling in adolescent MDD by integrating both diffusion magnetic resonance imaging (MRI) and resting-state functional MRI data.

Design, setting, and participants: This cross-sectional study recruited participants aged 10 to 18 years from January 2, 2020, to December 28, 2021. Patients with first-episode MDD were recruited from the outpatient psychiatry clinics at The First Affiliated Hospital of Chongqing Medical University. Healthy controls were recruited by local media advertisement from the general population in Chongqing, China. The sample was divided into 5 subgroup pairs according to different environmental stressors and clinical characteristics. Data were analyzed from January 10, 2022, to February 20, 2023.

Main outcomes and measures: The SC-FC coupling was calculated for each brain region of each participant using whole-brain SC and FC. Primary analyses included the group differences in SC-FC coupling and clinical symptom associations between SC-FC coupling and participants with adolescent MDD and healthy controls. Secondary analyses included differences among 5 types of MDD subgroups: with or without suicide attempt, with or without nonsuicidal self-injury behavior, with or without major life events, with or without childhood trauma, and with or without school bullying.

Results: Final analyses examined SC-FC coupling of 168 participants with adolescent MDD (mean [mean absolute deviation (MAD)] age, 16.0 [1.7] years; 124 females [73.8%]) and 101 healthy controls (mean [MAD] age, 15.1 [2.4] years; 61 females [60.4%]). Adolescent MDD showed increased SC-FC coupling in the visual network, default mode network, and insula (Cohen d ranged from 0.365 to 0.581; false discovery rate [FDR]-corrected P < .05). Some subgroup-specific alterations were identified via subgroup analyses, particularly involving parahippocampal coupling decrease in participants with suicide attempt (partial η2 = 0.069; 90% CI, 0.025-0.121; FDR-corrected P = .007) and frontal-limbic coupling increase in participants with major life events (partial η2 ranged from 0.046 to 0.068; FDR-corrected P < .05).

Conclusions and relevance: Results of this cross-sectional study suggest increased SC-FC coupling in adolescent MDD, especially involving hub regions of the default mode network, visual network, and insula. The findings enrich knowledge of the aberrant brain SC-FC coupling in the psychopathology of adolescent MDD, underscoring the vulnerability of frontal-limbic SC-FC coupling to external stressors and the parahippocampal coupling in shaping future-minded behavior.

Figure 1.. Structural and Functional Connectivity (SC-FC) Coupling Differences Between Participants With Adolescent Major Depressive Disorder (MDD) and Healthy Controls (HCs)

A, Primary sensory cortex, cingulate cortex, and basal ganglia exhibited relatively high SC-FC coupling. Inferior parietal lobe (IPL), lateral temporal areas, precuneus (PCun), and hippocampus exhibited relatively low SC-FC coupling. B, Compared with HCs, participants with adolescent MDD presented significantly increased SC-FC coupling in subregions of postcingulate cortex and ventral occipital lobule. C, Regions with within-group differences in SC-FC coupling (false discovery rate [FDR]–corrected P < .05; 246 tests) are labeled. Dashed horizontal line indicates −log₁₀ uncorrected P = .05. D, Mean SC-FC coupling significantly increased in participants with adolescent MDD (FDR-corrected P < .05; 48 tests). The upper and lower bounds of the boxes represents the first and third quartile, respectively; horizontal lines, median values; whiskers, 1.5 × of upper and lower bounds of IQRs; and circles above and below boxes, outliers. DAN, dorsal attention network; DMN, default mode network; FPN, frontoparietal network; INS, insula; L, left; LIM, limbic network; pSTS, posterior superior temporal sulcus; R, right; SOM, somatosensory network; SUB, subcortical network; VAN, ventral attention network; VIS, visual network. eTable 1 in Supplement 1 provides details on brain subregions.

Figure 2.. Regional Structural and Functional Connectivity (SC-FC) Coupling Differences Among Clinical Subgroups

The upper and lower bounds of the boxes represents the first and third quartile, respectively; horizontal lines, median values; whiskers, 1.5 × of upper and lower bounds of IQRs; and circles above and below boxes, outliers. Partial η² of analysis of variance was mapped on the brain cerebral cortex, thresholding at false discovery rate–corrected P < .05. Shaded areas indicate brain regions with subgroup-specific changes in SC-FC coupling. eTable 1 in Supplement 1 provides details on brain subregions. MLE indicates major life event.

Figure 3.. Exploratory Analysis of Associations Between Structural and Functional Connectivity (SC-FC) Coupling and Clinical Symptom Measures

Violins represent null distributions of test statistics; horizontal lines in violin plots, empirical test statistics; The upper and lower bounds of the boxes represents the first and third quartile, respectively; horizontal lines, median values; whiskers, 1.5 × of upper and lower bounds of IQRs; and circles above and below boxes, outliers. DAN indicates dorsal attention network; DMN, default mode network; FPN, frontoparietal network; HAMA, 14-item Hamilton Anxiety Rating Scale; HAMD-17, 17- item Hamilton Depression Rating Scale; LIM, limbic network; SOM, somatosensory network; VAN, ventral attention network; VIS, visual network.